DK155934B - ANALOGY PROCEDURE FOR PREPARING CIS-BICYCLO-OE3.3.0AAOCTAND DERIVATIVES - Google Patents

Abstract

Cis-bicyclo[3.3.0]octane derivatives corresponding to the formula <IMAGE> (I) wherein R1 is hydrogen, a lower alkyl group or a cation and wherein R2 represents a cyclohexyl or an adamantyl group. In these compounds the phenyl radical may be arranged with respect to the double bond in the EZ- or in the E-configuration and at the carbon atom bearing the group R2 the molecule may have the RS- or S-configuration. The compounds are prepared by reacting compounds of the formulae <IMAGE> wherein R1 and R2 have the same meaning as above and R6 represents hydrogen or a protecting group. Medicaments containing these compounds act as inhibitors of blood platelet aggregation and (in higher doses) as blood pressure lowering agents.

Description

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The present invention relates to an analogous process for the preparation of novel cis-bicyclo [3.3.0] octane derivatives of the general Formula I: ho "" CX ch2 \ H COOR, / 1 C = C (I) 1 to H XC -R0 / \ 2

H 2 -OH

wherein the phenyl group with respect to the double bond exhibits EZ or E configuration, and with the C group carrying the R 2 atom there is an RS or S configuration and where is a hydrogen atom, a straight or branched alkyl group having 1-4 C atoms or a pharmaceutically acceptable cation and R 2 is a cyclohexyl group, a 4-methylcyclohexyl group or a 1-adamantyl group having the structure: R 3 R 5 where R 3, R 2 and R 5 are the same or different and are hydrogen or methyl; which method is peculiar to the characterizing part of claim 1.

The group R 1 is preferably a hydrogen atom, a methyl * or ethyl group or a sodium or potassium ion. Other suitable cations are known in particular from the prostaglandin or prostacyclin chemistry.

The group R2 is preferably a group: 2

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-O * 5 wherein R is hydrogen or methyl and a particularly preferred group represented by R 2 is an unsubstituted cyclohexyl group.

The compounds of formula I have valuable pharmacological effects, however, in particular, they act thrombocyte aggregation inhibitor, but also blood pressure lowering, and thus are of similar type of action as, for example, prostacyclin, but distinguish themselves compared to prostacyclin, for example, at a significantly higher stability.

Chemically relatively stable analogues to prostacyclin have been previously described, such as carbacycline (which, like the compounds of formula I, are derived from cis-bicyclo [3.3.0] octane), but also these compounds have in vivo like prostacyclin only a short duration of action. [see.

20 e.g. Whittle et al., Prostaglandins 19 (1980), 605-627, especially page 623]. Compared to these known compounds, the compounds of formula I surprisingly show not only a significantly longer lasting effect, but also a significantly greater distance between the doses which respectively cause aggression inhibition and cause blood pressure lowering. The compounds of formula I are therefore useful both for disease states where an aggregate inhibition without concomitant blood pressure lowering (e.g., hyperaggregability in coronary heart disease) is desired, and at 3Q higher doses in disease states, where are appropriate (e.g., peripheral arterial closure disease) ;, The effects described can be demonstrated, for example, through the 35 experimentally found values listed below.

Belgian Patent Specification No. 887,721 (Example 13) discloses, respectively, the E · and · Z forms of 1,5-inter-m-phenylene-2,3,4-trinorcarbacycline, i.e. of 3- (m-carboxybenzylidene) - 3

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6β- (3'S-hydroxy-1Έ-octenyl) -7α-hydroxy-cis-bicyclo- [3.3.0] octane. The EZ form of this compound (hereinafter referred to as "Compound A") has been used in some of the experiments described herein as further Comparative Compound 5, which surprisingly showed a superior thrombocyte aggregation inhibitory and blood pressure lowering effect for the compounds of Formula I, particularly those where is a cyclohexyl group, compared to "Compound A".

The enzyme adenylate cyclase catalyzes the formation of 10 cyclic 31,5'-adenosine monophosphate (c-AMP) from adeno-sin triphosphate (ATP). If adenylate cyclase in thrombocytes is stimulated by compounds such as prostacyclin, a significant increase of the c-AMP mirror occurs in the platelets, thereby counteracting an aggregation of the platelets. The following Table 1 indicates the degree of stimulation of adenylate cyclase in equine platelets with some of the compounds of Formula I compared to the effect triggered by 5,6'-dihydroprostacycline or Compound A; 20

Table I

. Connection . EC.2: QQg .. [ymo.l / L.]. Relative effect 5,6-Dihydro-prostacycline 15.0 1.0

Compound A 0.40 37.5

Example Ie 0.15 100.0

Example 2 0.13 115.4

Example 3e 0.18 83.3 30 --- * The dose causing 3-fold stimulation of c-AMP formation from ATP.

For example, the in vitro aggregation of human thrombocytes mediated by arachidonic acid may be inhibited by prostacyclin. The following Table II indicates the IC ^ value (i.e. the concentration which causes a 50% inhibition of platelet aggregation under the test conditions) and the relative effect of prostacyclin calculated for some known compounds as well as for 4

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the products of Examples 1e and 2:

Table II

5 Compound IC ^ q Relative effect

Prostacycline 0.0078 1.0 5,6-Dihydro-prostacyclin 0.18 0.043

Compound A 0.12 0.065 Example 1 0.08 0.098

Example 2 0.07 0.11 In this connection it should be noted that Whittle et al.

15 (loc. Cit., Page 611) for carbacycline found that this as inhibitor of platelet aggregation in vitro by the aggregation induced by arachidonic acid showed only an effect of 0.02 times the prostacyclin action.

Table III indicates the effect of some compounds 20 against the in vivo ADP-induced thrombocytopenia on anesthetized rats (urethane anesthesia) by intravenous use of the test compounds.

Table III

25) __ i_. Connection . Relative effect

Dihydroprostacyclin 1.0

Compound A ..... 0.1 ^ Example 1e 1.0

Example 2 1.0

Tables I-III show the superior platelet count.

However, as already mentioned, these compounds do not function at a higher dose of lowering blood pressure, as shown in Tables IVa and IVb (wherein ED2Q

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5 is the dose which causes a decrease in diastolic blood pressure of 20 mm Hg):

Table IVa 5 Blood pressure lowering effect in adult, spontaneously hypertonic rats (measurement over permanent catheter, intravenous use of test compounds):

Compound EJD20 Relative Effect 5,6-Dihydro-prostacyclin 0.005 1.0

Compound A 1.9 0.003

Example le 0.073 0.068

Example 2 0.094 0.053 Example 3 e> 1.0. .... <0.005

Table IVb

Blood pressure lowering effect on pentobarbital 20 anesthetized rats (intravenous use of the test compounds):

Compound ED20. Relative effect

Prostacycline 0.16 1.0 Example. 2 ........... 5.39. 0.03

It is seen that the compounds of Formula I have superior blood pressure lowering effect over Compound A.

Prostacycline and carbacycline are rapidly converted to inactive products in vivo and therefore show only a very short duration of action. In comparison, the compounds of formula I appear to be considerably longer, as shown in the following table:

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Table V

Following intravenous use of a supramaximal hypotensive dose (1 mg / kg). on pentobarbital anesthetized rats, the following stepping characteristics were found for the blood pressure lowering effect;

Connection Step-down rate Half-life for blood pressure-lowering blood pressure .............. know, effect. . . . effect .......

1Q -----

Prostacycline 11.0% / min 5 5.89 min.

Example. 2 ......... 2., 6.% / Min ......... .2.5., 9.6. mine.

From this it can be seen that the product of Example 2 works for approx. 5 times longer than prostacyclin. Also, with respect to the platelet aggregation inhibitory effect, the significantly longer duration of action of the product of Example 2 could be demonstrated experimentally. To this, the compound was administered orally at a dose of 4.64 mg / kg orally to ure-20 than-anesthetized rats, and then the time course of the platelet aggregation inhibitory effect (ADP aggregation in vivo, measurement parameter: ADP-induced decrease in platelet count) with Technicon Auto Counter The following table indicates the percentage aggregation inhibition at the different measurement times:

Time after use (min, I

.................. 3.0 ...... 6.0. . '. . 1:50 .....

. %. Aggr.e.g.ationshæmning. . . ...... .3.8 2.6 2.2 ....... .....

30 -—: -—---

Thus, after oral administration, a pronounced antithrombotic aggregation inhibitory effect of the product of Example 35 2 could be observed for at least over 2.5 hours, while, for example, for prostacyclin, it is known to be inactive after oral use.

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As the compounds of formula I are not only characterized by surprisingly valuable biological properties, but also by good chemical stability, they are suitable both for parenteral and oral use to inhibit platelet aggregation in humans, and thus for the prevention and treatment of disease states, wherein platelet aggregation and / or a hyperaggregability pathogenetic is of importance. Such disease images are, for example, arterial thromboses in endothelial lesions, 10 atherosclerosis, haemostatic arterial and venous thromboses, and myocardial infarction. Because of their effect on blood pressure, the compounds of formula I are also considered for the treatment of pulmonary and systemic high pressures. The novel compounds can also advantageously be used to decrease the aggregability of extracorporeal blood circuits (artificial kidney, cardiac lung machines, etc.), where the compounds are added to the patient blood at micromolar concentrations.

Furthermore, the compounds of formula I cause a 2Q decrease in gastric acid secretion. Therefore, they are also considered for the treatment of elevated gastric acid secretion diseases, such as stomach and tarimilcus, but also for the treatment of other ulcer diseases such as anti-phlogisticaulcus.

The compounds of formula I are therefore used for the preparation of medicaments containing as active substance one or more of the compounds. The active ingredient content per single dose ranges from 0.01-50 mg, namely in preparations for parenteral use of 0.01-30 10 mg and in preparations for oral use of 0.1-50 mg.

Drugs for parenteral use may be solutions or suspensions or also spray products, e.g. for intranasal use, but may also be readily reconstitutable dry preparations, such as in single pack 35 lyophilized sodium salts of the compounds of formula I.

For oral use, these may be tablets, dragees or capsules in which the active substance may be administered.

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8 or more may be mixed or processed with conventional carrier materials, tablet explosives and binders. Such oral formulations may also be prepared in the usual manner such that they release the active ingredient in order to ensure a uniform supply of the active substance to the patient over a long period of time.

In this case, it is possible to increase the above single doses, e.g. to 100 or 250 mg per single form of the retarding composition, provided that the release rate 10 is such that the blood level of active substance is not higher than when oral use of a non-retarded formulation,

The preparation of these drugs takes place in a manner known per se, of course, in the preparation of parenterally usable preparations, sterility and - when in liquid form - isotony must be provided.

The compounds of formula I are prepared according to the invention in that a compound of general formula 20 II:

Rs ° '°'

c = c '(III

/ \ H C-R, 25

H OH

wherein R 2 is as defined above and R 9 is a hydrogen atom or a protecting group which is deprotected under mild conditions, excluding moisture and oxygen, in the presence of an aprotic solvent at temperatures of about 100 DEG.

0 ° C to approx. 100 ° C is reacted with a compound of formula III: 35 (C 6 H 5) 3 P = CH

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wherein R 2 is as defined above, where when R 9 is different from hydrogen, the protecting group R 9 is cleaved, and, if necessary, on the won compound of formula I, where R 2 is a hydrogen atom, esterification of the carboxyl group to a group is carried out. COOR 1, wherein R 2 is a (C 1 -C 4 alkyl group) or when R 1, wherein there is a (C 1 -C 2) alkyl group, saponification of the group COOR 2 to a carboxyl group and a product obtained (with R ^ = H), if desired, is then transferred into a pharmaceutically acceptable salt.

Preferred protecting groups represented by Rg of formula II are a tetrahydropyranyl group or a trialkylsilyl group containing in the alkyl groups a total of 3-6 C atoms, but also, for example, a benzoyl or 15 p-phenylbenzoyl group and others within the prostaglandin chemistry usual protecting group. come into consideration.

The reaction of the compound of general formula II with the compound of formula III takes place under careful exclusion of humidity and under an atmosphere of protective gas (suitable protecting gases are in particular argon or nitrogen), in the presence of inert, aprotic solvents such as benzene , toluene, dimethylsulfoxide or dimethylformamide at temperatures · from about 25 0 ° C to approx. 100 ° C, preferably in benzene and at temperatures from 20 ° C to 60 ° C and conveniently with the addition of a suitable amount of a weakly acidic compound such as thiophenol, p-chlorotriophenol or thiocresol.

Thereby the compound of formula I is obtained in the form of an EZ-isomer mixture. If R ^ is therein a (CC-C ^) alkyl group, the COOR₂ group, optionally after prior isomer separation, can be saponified to a carboxyl group (R ^ = H) and the product thus obtained, if desired, is transferred into a pharmaceutically acceptable salt. It is also possible to first perform the saponification or salt formation and only then to separate the isomers. However, if hydrogen is present and products of formula I are desired, wherein 10

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is an alkyl group as defined above, the product first obtained, optionally after prior isomer separation, may be esterified in the usual manner.

The separation of the E and .Z isomers is preferably carried out by high pressure liquid chromatography ("HPLC") in the usual manner using, for example, methanol / water (80:20). as eluent.

The phosphine alkylene of the general formula III can be prepared by reacting in a manner known per se 10 [cf. eg. Houben-Weyl "The Method of Organic Chemistry", Vol. 5/4, Stuttgart 1960, page 337, or R.C.Fuson et al., J.Am.Chem.Soc. 6_2 (1940) 1180] obtained phosphonium salt of the formula: (C 6 H 5) 3 P®-CH 2 chlorine or bromine, with a strong base such as potassium tert.butylate, methanesulfinyl sodium, potassium or lithium or especially sodium bis- (trimethylsilyl) amide, working in carefully dried solvents such as benzene , toluene, dimethylsulfoxide, hexamethylphosphoric triamide or tetrahydrofuran at temperatures from 0 100 ° C, preferably 20 to 80 ° C. Thereby, it is not necessary to isolate the compounds of formula III prior to reaction with the compound of formula II.

The preparation of the starting compounds of the general formula II wherein R 9 is hydrogen is preferably carried out in the reaction scheme shown below (with Z in the indicated formulas except hydrogen having the same meaning as R 9 and R defined):

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11 z- ° - <lX3 rv

CHO

{CH30) 2PO-CH2-CO-R2 V V

2- ° - <ιΧ3 "

CH = CH

O = C-R2

Nabha

Ζ- ° ~ <ΧΧ0] VII

/ CH = CH \ / 1 \ h / j-j C R 2 z X-y °] ° H H0 - n> 0 I '0 VIII II (RS) Tu-ru

CH = CH CH-CH

I \ / I

H - C - R, \ H / H ^ C - R 2

OH \ / OH

HO --- <^ I Vo V ^ 'y II (S)

CH = CH I

H-C-R2

0H

12

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To this should be added the following explanations:

The aldehyde IV with, for example, Z = tert-butyl-dimethylsilyl, i.e. 3,3-Ethylenedioxy-6β-formyl-7α-tert.butyl dimethylsilyloxy-cis-bicyclo [3.3.0] octane (Nicolaou et al., J. Chem. Soc., Chem. Commun. 1978 (1067) is reacted in a manner known per se with a phosphonate of general formula V to a ketone of general formula VI. The reaction takes place under careful exclusion of humidity and under a protective atmosphere such as argon or nitrogen. As a solvent, e.g. benzene, toluene, dimethoxyethane, dioxane or tetrahydrofuran. The reaction takes place at temperatures between ca. -20 ° C to 100 ° C, preferably between 0 ° C and 25 ° C within a period of approx.

2-24 hours.

The reduction of the thus obtained keto compounds VI takes place by reaction with complex borohydrides, such as sodium borohydride, with the addition of Cer-III salts being advantageous. The reaction takes place between -40 ° C and 60 ° C, preferably between 0 ° C and 25 ° C.

The obtained epimeric mixture VII can be divided by column chromatography on silica gel 60 with a suitable eluent mixture into the S and R forms respectively, the latter of which is of no interest here.

The cleavage of the protecting groups, ie. The catalytic group and the t-butyldimethylsilyl group preferred for Z take place in acetic acid medium (glacial acetic acid / water / tetrahydrofuran 3: 1: 1) at approx. 25 ° C [Corey et al., J. Amer.chem.Soc. 94, 6190 (1972), Nicolaou et al., J. Chem.

Soc., Chem. Commun. 1978, 1067], thereby winning the S-form 30 for the compounds of the general formula II.

However, it is also possible first to remove from the epimer mixture VII the protecting groups and then divide the epimer mixture of the general formula II (RS) by column chromatography, e.g. on silica gel 60 to give 35 of the isomeric II (S). To prepare the 3'-RS form of the compounds of formula I, the isomer mixture II (RS) is used as starting material, optionally after the introduction of a protecting group Rg, and this is reacted with the compound of formula III.

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13

For example, to prepare a compound of formula II wherein the group Rg is one of the defined protecting groups, in a compound of formula VII or VIII, the ethylenedioxy group may be selectively cleaved. However, it is also possible to proceed in the way that a protecting group Rg is introduced in the usual way into a compound of formula II wherein Rg is hydrogen.

The process according to the invention is further described by the following examples. In their implementation 10, no emphasis was placed on achieving maximum yields. All temperatures are uncorrected.

The reactions were followed by thin layer chromatogram (DC) (finished plates, silica gel 60, E.Merck).

Unless otherwise noted, silica gel 60, grain size 0.040-0.063 mm (230-400 mesh ASTM) from Macherey-Nagel was used for the column chromatography.

The mixing ratio of the eluent by the chroma tograf method is in volume / volume.

Ether (which is understood to mean diethyl ether everywhere) was distilled prior to use in eluant solvent for column chromatography.

1 13 The H-NMR 'spectra were recorded at 60 MHz and the C-NMR spectra at 15.08 MHz with the apparatus WP-60 from the company Bruker. The chemical shift is given in ppm.

25

Example 1 a) 3,3-Ethylenedioxy-6β- (3'-oxo-3'-cyclohexyl-1'E-propenyl). -7 α-tert. butyl-dimethylsilyloxy-cis-bicyclo [3.3.0] -octane, General Formula VI; R 2 = cyclohexyl Z = t-butyl-dimethylsilyl.

To a suspension of 28.3 mg of sodium hydride dispersion (50% in oil) in 15 ml of absolute dimethoxyethane, a solution of 139 mg of 2-oxo-2 was added dropwise with stirring and under argon as a protective gas 35 at room temperature. cyclohexyl-ethane phosphonic acid dimethyl ester in 2 ml of absolute dimethoxyethane and stirred for 45 minutes at room temperature. Then a 14 was added dropwise

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solution of 194 mg of 3,3-ethylenedioxy-6-formyl-7a-tert.-butyldimethylsilyloxy-cis-bicyclo [3.3.O] octane in 1 ml of absolute dimethoxyethane and stirred further under argon protection and at room temperature. After approx. for three hours, a solution of 34.4 μΐ glacial acetic acid in 400 µl of ether was added and the mixture was evaporated in vacuo. The slightly pale yellow oil obtained was taken up in 10 ml of ether and the ethereal solution was washed with 5 ml of saturated sodium bicarbonate solution as well as with 5 ml of saturated sodium chloride solution and dried over sodium sulfate and the solution was evaporated in vacuo.

The oily residue was purified by column chromatography. With ether / hexane (3: 2), 188 mg (73% of theory) of the title compound was obtained.

C 25 H 42 SiO 4: 434'702 1 H NMR (CDCl 3): 6.75 (2d, 1H), 6.15 (d, 1H), 3.93 (s, 4H), 3.89 (s, 1H), 0.95 (s, 9H), 0.8 (s, 6H).

b) 3,3-Ethylenedioxy-6β- (3′S-hydroxy-3′-cyclohexyl-1Έ-propenyl) -7α-tert.butyl-dimethylsilyloxy-cis-bicyclo- [3.3.0] octane.

General formula VIII: = cyclohexyl Z = t-butyl-dimethylsilyl.

To a solution of 1.36 g of the product obtained in Example 1a in 18 ml of methanol was added 7.8 ml of a 0.4M methanolic Cer-III chloride solution and 30 with stirring and cooling with ice, small portions added 118.5 mg of sodium borohydride. After completion of the addition, the mixture was stirred for an additional five minutes under ice-cooling and then allowed to stand at room temperature with stirring. After about 30 minutes, 31 ml of pH 7 buffer 35 was stirred and ca. 80 ml of methylene chloride as well as 50 ml of saturated potassium sodium tartrate solution, and the organic phase was separated and the aqueous phase was extracted three more times with each time approx. 50 ml of methylene chloride. The total methylene chloride

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15 riding solutions were washed with ca. 25 ml of saturated sodium chloride solution, the organic phase was dried over sodium sulfate and the solution was evaporated in vacuo.

The oily residue was purified by 5 column chromatography. With ether / petroleum ether (l.tl) · 516.2 mg (38% of theory) of the title compound, 111.4 'mg (8% of theory) of the corresponding 3'R isomer, and 472.3 mg (35%) were obtained. % of the theory.) of the 3'RS isomer mixture which could be further subdivided by chromatography.

C 25 H 44 SiO 4: 436.718 1 H-NMR (CDCl 3): 5.48 (m, 2H), 3.90 (s, 4H), 3.76 (m, 2H), 0.91 (s, 9H), 6 (s, 6H).

c) 6β- (3'S-Hydroxy-3'-cyclohexyl-1Έ-propenyl) -7α-hydro-xy-cis-bicyclo [3.3.0] octan-3-one.

General formula II: R 2 = cyclohexyl.

Of the compound obtained according to Example 1b, 516.2 mg was added to 5 ml of a mixture of glacial acetic acid / tetrahydrofuran / water (3: 1: 1) and stirred for approx. 20 hours at room temperature. (For reaction control was used as DC eluent ether / acetone 2: 1.) Then 20 ml of saturated sodium bicarbonate solution and solid sodium bicarbonate were gently added until the acetic acid was neutralized, then extracted three times with 10 ml of methylene chloride each time, methylene chloride solutions were washed with 10 ml of saturated sodium chloride solution, the organic phase was dried over sodium sulfate and the solution evaporated in vacuo.

The oily residue was purified by column chromatography. With ether / acetone (2: 1), 301 mg (92% of theory) of the title compound was obtained as colorless oil which slowly crystallized at room temperature.

Mp: 96-97.5 ° C.

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C 17 H 26 ° 3: 278.395 1 H-NMR (CDCl 3): 5.48 (m, 20), 3.88 (m, 20).

13 C NMR (methanol-d 4): 222.52, 134.76, 133.78, 79.01, 78.34, 58.49, 46.63, 45.04, 44.31, 43.52, 42, 43, 36.28, 30.01, 27.70, 27.21.

D) 3- (m-Methoxycarbonylbenzylidene) -6β- (31S-hydroxy-31-cyclohexyl-1Έ-propenyl) -7α-hydroxy-cis-bicyclo [3.3.0] octane.

General formula I: R 2 = CH 2, R 2 = cyclohexyl.

To a suspension of 2.141 g of sodium bis (trimethylsilyl amide in 20 ml of absolute benzene) was added 5.743 g of m-methoxycarbonylbenzyltriphenylphosphonium bromide with stirring, at room temperature and with the exclusion of humidity and nitrogen as protective gas. 30 minutes at room temperature and heated to reflux for 1 hour, allowed to cool to room temperature, then a solution of 224.3 mg of the product obtained in Example 1c in 5 ml of absolute benzene and 154 µl of 25 thiophenol was added. The mixture was first stirred at room temperature for one hour and then at 50-60 ° C for one week (DC eluent: ether / ethyl acetate 4: 1).

The reaction mixture was stirred with 100 ml of water, the benzene layer was separated, the aqueous layer was extracted three times with 25 ml of ether each time, the combined organic phases were washed with 25 ml of saturated sodium chloride solution, dried over sodium sulfate and the solution was evaporated in vacuo.

The oily residue was purified by column chromatography. With ethylene / ethyl acetate (4: 1), 145 mg (44% of theory) of the 3EZ form of the title compound was obtained as a colorless oil.

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1 H NMR (CDCl 3): 7.77 (m, 2H), 7.32 (m, 2H), 6.37 (s, extended, 1H), 5.49 (m, 2H), 3.92 (s, 3H), 3.70 (m, 2H).

5 A division into the Z and E isomers was obtained by HPLC on a Reversed Phase column [LiChrosorb RP 80 10 µm (Knaur) as column material, column diameter 4.6 mm, flow rate 2 ml / min]. With methanol / water (8: 2) as eluant, from 65 mg of EZ mixture 15.6 mg of the Z-isomer and 28.2 mg of the desired E-isomer of the title compound having m.p. 126.5-128 ° C and showed the following spectrum values: 26 26 ^34 ^4 * 410.559 hl H NMR (CDCl3; 7.77 (m, 2H), 7.32 (m, 2H), 6.37 (s 1H), 5.49 (m, 2H), 3.94 (s, 3H), 3.70 (m, 2H).

20 C NMR (methanol-d 4): 148.39, 140.30, 134.82, 134.33, 134.09, 131.23, 130.31, 129.40, 127.94, 122.58 , 78.58, 78.34, 57.76, 52.59, 45.71, 45.04, 42.79, 41.15, 39.87, 38.90, 30.13, 27.70, 27.21.

E) SEZ-1-Carboxy-benzylidene-1-ep-P'S-hydroxy-5'-cyclohexyl-1'-propenyl) -7a-hydroxy-cis-bicyclo [3.3.0] -octane.

General Formula I; = H, R 3 = cyclohexyl.

To a solution of 145 mg of the product obtained in Example 1 35 in the 3EZ form in 5 ml of methanol was added 2 ml of 1 N sodium hydroxide solution and stirred for 2 hours at room temperature (DC eluent: ether / acetone 9: 1). . It was recommended overnight at room temperature.

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18 perature, with stirring added 2.2 ml of 1N hydrochloric acid, extracted three times with 10 ml of methylene chloride each time, the combined methylene chloride solutions were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate and the solution was evaporated in vacuo.

106 mg (76% of theory) of the title compound was obtained as a colorless oil which solidified at room temperature.

Δ: 396.532 1 H NMR (CDCl 3): 7.85 (m, 2H), 7.37 (m, 2H), 6.33 (s wides, 1H), 5.46 (m, 2H), 3.67 (m, 2H), 3.08 (s, 3H, interchangeable with D 2 O).

f) This compound can be transferred into its sodium salt (R- = Na) as given below:

To a solution of 70.2 mg of the carboxy compound 20 in 5 ml of methanol was added, with stirring, a solution of 29.8 mg of sodium bicarbonate in 3 ml of water and allowed to stand overnight and heated for an hour at 60 ° C. The solution was evaporated in vacuo and to the residue was added an additional 10 ml of methanol and evaporated again in vacuo. The dry evaporation residue was extracted three times with each 5 ml of methanol, the methanolic solution was filtered and the filtrate was evaporated in vacuo.

70.5 mg (95% of theory) of the sodium salt were obtained in the form of slightly yellowish crystals, C 25 H 31 ° 4Na 418t514 1 H NMR (methanol-d41; 6.44 (s wides, 1H), 35 5.49 (m, 2H).

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Example 2 3E- (m-Carboxy-benzylidene) -60- (3'S-hydroxy-31-cyclohexyl-1'-propenyl) - * 7α-hydroxy-cis-bicyclo [3.3.0] octane.

General Formula I: R f = H, R f = cyclohexyl.

From 86 mg of the product obtained in Example 1 in the 3E form in 12 ml of methanol and 3 ml of 1 N sodium hydroxide solution, analogously to Example 1e, 78.5 mg (95% of the theory of the title compound as colorless oil crystallizing) was obtained. mp: 161-164 ° C.

C 25 H 32 ° 4: 396'532 1 H'-NMR (CDCl3); 7.90 (m, 2H), 7.43 (m, 2H), 6.37 (s widespread, 1H), 5.51 (m, 2H), 3.78 (m, 3H).

Example 3 Al 3,3-Ethylenedioxy-60- [3 '-oxo-31 - (1 "-adamantyl) -11E-propenyl] -7a-tert.butyl-dimethylsilyloxy-cis-bicyclo-20 [3.3.0 ] octane.

General Formula VI: R 2 = 1-adamantyl Z = t-butyl ~ dimethylsilyl.

242.6 mg of sodium hydride dispersion (50% Si oil) in 20 ml of absolute toluene were reacted analogously to Example 1a with 1.47 g of 2'-oxo-2 - * - (1,1 * - adamantyl ethanophosphonic acid methyl ester) in 40 ml of absolute toluene and 1.5 g of 3,3-ethyl-endioxy ^ 63-formyl ^ 7a-tert.butyl ^ dimethylsilyloxy-cis-bi-cyclo [3.3.0] octane in 5 ml of absolute toluene. here, stirred for 6 hours and left to stand overnight in a refrigerator (DC eluent: ether / hexane 1: 1).

After column chromatography with petroleum ether / ether (4; 11), 999.1 mg (45% of theory) of the title compound, 35 C 29 H 46 SiO 4

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HI NMR (CDCl3): 6.61 (m, 2H), 3.88 (s, 4H), 3.76 (m, 1H), 0.88 (s, 9H), 0.03 (s, 6H).

The 2-oxo-2- (1,1-adamantyl) -ethane-phosphonic acid dimethyl ester used above was obtained as follows:

To 45 ml of dry ether was stirred in a nitrogen atmosphere at ca. -70 ° C was added dropwise 77.5 ml of a 15% 1s solution of n-butyllithium in hexane, then a solution of 10.8 ml of methane phosphonic acid methyl ester in 50 ml of dry tetrahydrofuran was added. Stir for 15 minutes, dropwise add a solution of 10.4 g of 1-adamantane carboxylic acid ethyl ester in 50 ml of dry tetrahydrofuran at -75 ° C and stir for 3 hours. The reaction mixture was allowed to reach 0 ° C during the night and, by careful addition of 4N hydrochloric acid at 0 ° C, was adjusted to pH 4-5.

The solution was evaporated in vacuo, the residue was taken up in 100 ml of ethyl acetate and washed three times with 30 ml of saturated sodium chloride solution each time.

The combined washings were extracted twice with 10 ml of ethyl acetate each time and the organic phases were combined. It was dried over sodium sulfate and the solution was evaporated in vacuo. The oily residue was distilled in vacuo to give 10.4 g (72% of theory) of the product as colorless oil.

Bp: 170-171 ° C / 0.2 mm Hg 1 H NMR (CDCl 3): 3.86 (s, 3H), 3.67 (s, 3H), 3.31 (s, 1H), 2 , 96 (s, 1H), 1.94 (m, 15H).

b) 3,3-Ethylenedioxy-6β- [3'S-hydroxy-3 '- (1 "-adamantyl) -35'-propenyl] -7a-tert-butyl-dimethylsilyloxy-cis-bi-cyclo [3.3.0 ] octane.

General formula VIII: R 2 = 1-adamantyl Z = t-butyl-dimethylsilyl.

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21

Analogously to Example 1b, 422.5 mg of the product of Example 3a was obtained in 5 ml of methanol and 2.6 ml of 0.4M methanolic Cer-III chloride solution and 51.3 mg of sodium borohydride after column chromatography with petroleum ether / 5 ether ( 2: 1) 314.1 mg (74% of theory) of the title compound and 56.9 mg (13% of theory) of the corresponding 3'E isomer discarded.

C29H48Si04; 488'794 S's-1- Isomer: 1 H NMR (CDCl 3): 5.50 (m, 2H), 3.93 (s, 4H), 3.70 (m, 2H), 0.93 (s, 9H), 0.08 (s, 6H).

13 C NMR (methanol-d 4); 134.88, 130.37, 119.97 82.05, 80.28, 65.37, 64.76, 58.07 43.95, 20 43.10, 42.49, 40.91, 39.26, 38 , 29, 37.80, 36.77, 29.58, 26.48, 18.81.

C). 6β- [3′S-Hydroxy-3,3- (1 "-adamantyl) -1,1-propenyl] -7a-hydroxy-cis-bicyclo [3,3,0] octan-3-one.

General formula II; r 2 = 1-adamantyl.

Analogously to Example 1c, 314.1 mg of the product of Example 3b was obtained after column ether / acetone (3: 1) column chromatography 192.2 mg of the title compound as white crystals.

Mp: 142-143.5 ° C (of diisopropyl ether).

C 21 H 30 ° 3 * 330'471 H NMR (CDCl3); 5.52 (m, 2H), 3.95 (m, 1H), 3.53 (m, 1H).

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22 d) 3EZ- (m-Methoxycarbonylbenzylidene) -63 "[31S-hydroxy-31 - (1" -adamantyl) -1Έ-propenyl] -7ot-hydroxy-cis-bi-cyclo [3.3.0] octane.

General formula I: R 2 = CH 3, R 2 = 1-adamantyl.

Analogously to Example 1d, 195.9 mg of the i

Example 3c obtained product, 2.91 g of m-methoxycarbonyl-benzyl-triphenylphosphonium bromide and 1.09 g of sodium bis- (trimethylsilyl) -amide reacted mutually. After column chromatography with ether / acetone (4: 1), 114.4 mg of the title compound (42% of theory) was obtained as a solid.

1 H-NMR (CDCl 3): 7.86 (m, 2H), 7.36 (m, 2H), 6.35 (s wides, 1H), 5.50 ( m, 2H), 3.88 (s, 3H), 3.80 (m, 2H), e). 3EZ- (m-Carboxy-benzylidene) -6β- [31 S-hydroxy-3 '- (1' - 20-adamantyl) -1Έ-propenyl] -7a-hydroxy-cis-bicyclo- [3.3.0] octane.

General formula I: R 2 = H, R 2 = 1-adamantyl.

Analogously to Example 1c, 110.4 mg of the product obtained in Example 3d was obtained in 10 ml of methanol and 3 ml of 25 IN sodium hydroxide solution 79.3 mg of the title compound (74% of theory) as a solid, C29H36 ° 4: 448 1 H-NMR (CDCl 3): 7.83 (m, 2H), 7.37 (m, 2H), 6.37 (s wides, 1H), 5.48 (m, 2H) , 3.47 (m, 2H)., 3.25 (s, 3H, interchangeable with D 2 O).

Example 4

The same procedure as in Examples 1-3 was used and extracted from the corresponding starting materials; 23

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a) 3E- (m-Ethoxycarbonylbenzylidene) -6β- (3'S-hydroxy-3'-cyclohexyl-1'E-propenyl) -7a-hydroxy-cis-bicyclo- [3.3.0] octane,

General Formula I; = C 2 H 2 - 2 = cyclohexyl.

C 27 H 36 ° 4: 424/586 Mp: 115-116 ° C, 1 H NMR (CDCl 3); 7.78 (m, 2H), 7.30 (m, 2H), 6.31 (s widespread, 1H), 5.48 (m, 2H), 4.23 (q, 2H), 3.70 ( m, 2H), 1.38 (t).

B1 3E ^ [m- (n ~ Propyloxycarbonyl) »-benzylidene] -63- (3 'S-hydroxy ^ 3' 'cyclohexyl-1'E ^ propenyl) -7 α-hydroxy-cis-bicyclo [3.3.0 ] octane.

General Formula I; R 2 = ηΚ ^ Η 2, R 2 = cyclohexyl.

C2gH3804; 438613

m.p .; 68-71 ° C.

1 H-NMR (CDCl 3); 7.78 (m, 2H1, 7.32 (m, 2H), 6.33 (s wides, 1H), 5.43 (m, 2H1, 4.23 (t, 2H)) , 3.64 (m, 2H).

C1 Sodium furosalt of 3E - * - (m, '' carboxybenzylidene) ~ 6β- (3, S-hydroxy-3 '' - cyclohexyl ^ -1'E-propenyl) -7a-hydroxy-cis -blycyclo [3, 3,0] octane ..

General Formula I; R 1 = Na, R 2 = cyclohexyl C 25 H 31 ° 4 Na; 1 H-NMR (methanol-d 4); 6.44 (s widespread, 1H), 5.51 (m, 2H1.

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24 d) 3E- (m-Carboxybenzylidene) -63- [31S-hydroxy-3 '- (adamethyl-1 ") -1β-propenyl] -7a-hydroxy-cis-bicyclo [3.3.0] -octane .

General Formula I: R 1 = H, R 2 = -1-adamantyl C 29 H 36 ° 4: 448'609 1 H-NMR (methanol-d 4): 7.78 (m, 2H), 7.37 (m, 2H), 6.38 (s widespread, 1H), 5.50 (m, 2H).

e) 3EZ- (m-Carboxybenzylidene) -6β- [3'S-hydroxy-31- (3 ", 5" -dimethyladamantyl-1 ") -1'-propenyl] -7a-hydroxy-cis-bicyclo [3.3.0] octane .

General formula X: = H, R 2 = 3,5-dimethyladamantyl-1.

C31H40 ° 4! 476'663 1 H NMR (CDCl 3): 7.78 (m, 2H), 7.32 (m, 2H), δ 6.30 (s, widespread, 1H), 5.41 (m, 2H), 3 , 86 (s, 3H), 3.65 (m, 2H).

f) 3E- [m- (tert-Butyloxycarbonyl) benzylidene] -6β- (3'S-hydroxy-3'-cyclohexyl-1Έ-propenyl) -7α-hydroxy-cis-bicyclo [3.3.0] octane.

General formula I: R 2 = (CH 2 J 2 C-, R 2 = cyclohexyl.

H-NMR (CDCl3): (recorded at 300 MHz): δ 7.88 (s, 1H), 7.80 (m, 1H), 7.37 (m , 2H), 6.43 (s, widespread, 1H), 5.55 (m, 2H), 3.77 (m, 2H), 1.60 (s, 9H).

g) 3E- (m-Carboxybenzylidene) -6β- [3 * S-hydroxy-3 '- (4 "- methyl-cyclohexyl) -1Έ-propenyl] -7a-hydroxy-cis-bicyclo [3.3.0] octane .

General formula I: = H, R 2 = 4-methylcyclohexyl.

Claims (3)

General formula I: = K, R 2 = cyclohexyl C 25 H 31 OK: 434'624 1 H NMR (methanol-d4): 6.44 (s, widespread, 1H), 5.51 (m, 2H). 15 1. Analogous Process for Preparing Cis-Bicyclo [3.3.0] Octane Derivatives of General Formula I: 20 / -V HO - / 1 y = CH \ C = C'B COOR, (I) H "> * 2 o . / \ 25. OH wherein the phenyl group with respect to the double bond exhibits EZ or E configuration and there is present at that group carbon-bearing carbon atom RS or S configuration and where R1 is a hydrogen atom, a straight or branched alkyl group with 1-4 C atoms or a pharmaceutically acceptable cation, and R 2 is a cyclohexyl group, a 4-methylcyclohexyl group 35 or a 1-adamantyl group having the structure: R 3, R 4 and R 3 are the same or different and is hydrogen or methyl, characterized in that a compound of the general formula II: Re C = (TH (III Λ * 2 H OH where: 20 1 * 2 is as defined above) and Rg is a hydrogen atom or a protecting group which is clearable under mild conditions, excluding moisture and oxygen, in the presence of an aprotic solvent at temperatures from about 25 ° C to about 100 ° C is reacted with a compound of formula III: (c6h5) 3p = ch.Q (III) COOR-1 wherein R 1 is as defined above, where when R 9 is different from hydrogen, the protecting group R 9 is cleaved and, if necessary, on the 35 compound of formula I, where R 1 is a hydrogen atom, esterification of the carboxyl group to a group COOR-j where is a (C 1 -C 4 alkyl group) or when R 1 is a (C 1 -C 4) alkyl group, saponification of the group DK 155934B COOR.J into a carboxyl group and a product obtained (with R 2 = H), if desired, then transferred into a pharmaceutically acceptable salt. Process according to claim 1, characterized in that the reaction is carried out with the addition of a weakly acidic compound, in particular an optionally substituted thiophenol. Process according to claim 1 or 2, characterized in that R 9 is a tert-butyldimethylsilyl group.